scholarly journals Pharmacological modulation of AMPA receptors rescues specific impairments in social behavior associated with the A350V Iqsec2 mutation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Renad Jabarin ◽  
Nina Levy ◽  
Yasmin Abergel ◽  
Joshua H. Berman ◽  
Amir Zag ◽  
...  

AbstractIn this study we tested the hypothesis that pharmacological modulation of glutamatergic neurotransmission could rescue behavioral deficits exhibited by mice carrying a specific mutation in the Iqsec2 gene. The IQSEC2 protein plays a key role in glutamatergic synapses and mutations in the IQSEC2 gene are a frequent cause of neurodevelopmental disorders. We have recently reported on the molecular pathophysiology of one such mutation A350V and demonstrated that this mutation downregulates AMPA type glutamatergic receptors (AMPAR) in A350V mice. Here we sought to identify behavioral deficits in A350V mice and hypothesized that we could rescue these deficits by PF-4778574, a positive AMPAR modulator. Using a battery of social behavioral tasks, we found that A350V Iqsec2 mice exhibit specific deficits in sex preference and emotional state preference behaviors as well as in vocalizations when encountering a female mouse. The social discrimination deficits, but not the impaired vocalization, were rescued with a single dose of PF-4778574. We conclude that social behavior deficits associated with the A350V Iqsec2 mutation may be rescued by enhancing AMPAR mediated synaptic transmission.

2020 ◽  
Author(s):  
Renad Jabarin ◽  
Nina Levy ◽  
Yasmin Abergel ◽  
Joshua H. Berman ◽  
Amir Zag ◽  
...  

AbstractIn this study we tested the hypothesis that precision medicine guided therapy targeting glutamatergic neurotransmission could rescue behavioral deficits exhibited by mice carrying a specific mutation in the Iqsec2 gene. The IQSEC2 protein plays a key role in glutamatergic synapses and mutations in the IQSEC2 gene are a frequent cause of neurodevelopmental disorders. We have recently reported on the molecular pathophysiology of one such mutation A350V and demonstrated that this mutation downregulates AMPA type glutamatergic receptors (AMPAR) in A350V mice. Here we sought to identify behavioral deficits in A350V mice and hypothesized that we could rescue these deficits by PF-4778574, a positive AMPAR modulator. We found that A350V Iqsec2 mice exhibit specific deficits in sex preference and emotional state preference behaviors as well as in vocalizations when encountering a female mouse. The social discrimination deficits, but not the impaired vocalization, were rescued with PF-4778574. We conclude that social behavior deficits associated with the A350V Iqsec2 mutation may be rescued by enhancing AMPAR mediated synaptic transmission.


2020 ◽  
Vol 75 (3) ◽  
pp. 425-454
Author(s):  
Hámori Eszter ◽  
Simon Réka Barbara ◽  
Márkus Lilla Viktória ◽  
Farkas Flóra

Háttér és célkitűzések:A fapofa-paradigma (Tronick, Als, Adamson, Wise és Brazelton 1978) szokatlan megszakításos helyzetet teremt az anya-csecsemő interakcióban, így az egyik leggyakrabban alkalmazott eljárás az egyéni és a diádikus társas és stressz-szabályozási minták vizsgálatában csecsemőkorban. A kódrendszerek sokfélesége miatt azonban ellentmondásosak az eredmények a mintázatok azonosításában. Jelen tanulmányban egyik célunk egy olyan globális kódrendszer kialakítása volt, amellyel külön vizsgálhatjuk a társas viselkedés és az érzelemkifejezés szerepét a regulációs mintázatok formálódásában. Másik célunk a fapofa- és a regulációs szakaszokra jellemző társasviselkedés-mintázatok keresése és a két szakasz közötti változásuk vizsgálata volt.Módszer:101 3–6 hónapos, tipikusan fejlődő csecsemő-anya párral vettük fel a fapofa-paradigmát. A csecsemők érzelmi állapotát, társas viselkedését és stressz-szintjének alakulását a jelen kutatásra kidolgozott Érzelmi és Társas Szabályozási Mintázatok Globális Kódrendszerével értékeltük a fapofa- és a regulációs szakaszokban.Eredmények:Az érzelmi dimenzió mintázatai egyértelműen mutatták a klasszikus fapofa-hatást a mintában. A társas dimenzióban négy fő mintázatot defi niáltunk: anyára pozitív, anyára negatív, anyára vegyes és minimalizáló. A fapofa-szakasz domináns társas mintázatai eltérően jósolták be a regulációs szakasz társas mintázatait. A társas viselkedés két szakasz közötti változásában a stressz-szinttel való összefüggésük mentén adaptív, rizikós és többesélyes mintázatokat azonosítottunk. Klaszterelemzéssel egy Nyugodt és egy Nyűgös csoport különült el, amiben az érzelmi dimenzió differenciáló szerepe emelkedett ki a társas dimenzióval szemben.Következtetések:Eredményeink alátámasztják, hogy már 3 hónapos kortól jelen lehetnek a stressz szabályozására specifi kus, egyéni regulációs mintázatok. Kódrendszerünk a globális dimenziók alkalmazásának fontosságára hívja fel a fi gyelmet, amely informálhat az összetett érzelmi, valamint a társasviselkedés-mintázatok és a stresszreguláció kölcsönkapcsolatáról, és így hozzájárulhat azok adaptív vagy maladaptív jellegének felméréséhez.Background and aims:The Face-to-Face-Still-Face Paradigm (FFSF, Tronick et al, 1978) artifi cially generates an unusual perturbation in the infant-mother interaction and as such has become a widely used procedure in the investigation of individual and dyadic social and stress regulation in infancy. The various coding systems, however, have brought about controversial results in the identifi cations of regulatory patterns. One of our aims was to develop a global coding system, by means of which the role of the social and emotional regulatory behaviors in the formations of organized regulatory patterns could be evaluated separately. Our second aim was to search for social behavior patterns exhibitive of the Still Face and Regulatory episodes as well as to examine their changes from one episode to to other.Method:The FFSF paradigm was administered to 101 typically developing 3-6 months-old infant-mother dyads. The emotional state, the social behavior and the changes in the stress level of the infant were evaluated in two episodes of the FFSFP by the Global Coding System of Emotional and Social Regulatory Patterns that has been developed for the purpose of this study.Results:The classical Still-Face effect has been clearly demonstrated by the results of the emotional state dimension. Beyond this, we identifi ed four social regulatory patterns: positive-to-mother, negative-to-mother, ambivalent-to-mother and minimization. The dominant social patterns in the Still-Face episode predicted variously those in the Reunion episode. Different patterns of the interrelations of the changes in social strategies and the stress level in the Reunion episode could be identifi ed as adaptive, risk and multi chance patterns. Two groups of infants have been separated by the cluster analysis, the calm and the fussy groups. Emotional dimension, as contrast to social dimension, has emerged as signifi cant clustering predictor. Conclusion: Our results support the hypotheses that individual stress regulatory patterns can be present from as early as three months of infant age. Our coding system draws attention to the importance of global behavioral coding dimensions that can inform us about the interconnection between the complex emotional and social behavior patterns and the stress regulation and thus can contribute to the exploration of their adaptive versus maladaptive nature.


2021 ◽  
Vol 15 ◽  
Author(s):  
Wen-Jun Gao ◽  
Nancy R. Mack

Abnormal social behavior, including both hypo- and hypersociability, is often observed in neurodevelopmental disorders such as autism spectrum disorders. However, the mechanisms associated with these two distinct social behavior abnormalities remain unknown. Postsynaptic density protein-95 (PSD-95) is a highly abundant scaffolding protein in the excitatory synapses and an essential regulator of synaptic maturation by binding to NMDA and AMPA receptors. The DLG4 gene encodes PSD-95, and it is a risk gene for hypersocial behavior. Interestingly, PSD-95 knockout mice exhibit hyposociability during adolescence but hypersociability in adulthood. The adolescent hyposociability is accompanied with an NMDAR hyperfunction in the medial prefrontal cortex (mPFC), an essential part of the social brain for control of sociability. The maturation of mPFC development is delayed until young adults. However, how PSD-95 deficiency affects the functional maturation of mPFC and its connection with other social brain regions remains uncharacterized. It is especially unknown how PSD-95 knockout drives the switch of social behavior from hypo- to hyper-sociability during adolescent-to-adult development. We propose an NMDAR-dependent developmental switch of hypo- to hyper-sociability. PSD-95 deficiency disrupts NMDAR-mediated synaptic connectivity of mPFC and social brain during development in an age- and pathway-specific manner. By utilizing the PSD-95 deficiency mouse, the mechanisms contributing to both hypo- and hyper-sociability can be studied in the same model. This will allow us to assess both local and long-range connectivity of mPFC and examine how they are involved in the distinct impairments in social behavior and how changes in these connections may mature over time.


2019 ◽  
Vol 60 (2) ◽  
pp. 303-305
Author(s):  
Valdir Leite da Silva ◽  
José Cândido ◽  
José Nelson Campanha ◽  
Doraci R. de Oliveira ◽  
Carla Gheler-Costa ◽  
...  

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kohei Kitagawa ◽  
Kensuke Matsumura ◽  
Masayuki Baba ◽  
Momoka Kondo ◽  
Tomoya Takemoto ◽  
...  

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.


Author(s):  
Ahmed Eltokhi ◽  
Miguel A. Gonzalez-Lozano ◽  
Lars-Lennart Oettl ◽  
Andrey Rozov ◽  
Claudia Pitzer ◽  
...  

AbstractMutations in SHANK genes play an undisputed role in neuropsychiatric disorders. Until now, research has focused on the postsynaptic function of SHANKs, and prominent postsynaptic alterations in glutamatergic signal transmission have been reported in Shank KO mouse models. Recent studies have also suggested a possible presynaptic function of SHANK proteins, but these remain poorly defined. In this study, we examined how SHANK2 can mediate electrophysiological, molecular, and behavioral effects by conditionally overexpressing either wild-type SHANK2A or the extrasynaptic SHANK2A(R462X) variant. SHANK2A overexpression affected pre- and postsynaptic targets and revealed a reversible, development-dependent autism spectrum disorder-like behavior. SHANK2A also mediated redistribution of Ca2+-permeable AMPA receptors between apical and basal hippocampal CA1 dendrites, leading to impaired synaptic plasticity in the basal dendrites. Moreover, SHANK2A overexpression reduced social interaction and increased the excitatory noise in the olfactory cortex during odor processing. In contrast, overexpression of the extrasynaptic SHANK2A(R462X) variant did not impair hippocampal synaptic plasticity, but still altered the expression of presynaptic/axonal signaling proteins. We also observed an attention-deficit/hyperactivity-like behavior and improved social interaction along with enhanced signal-to-noise ratio in cortical odor processing. Our results suggest that the disruption of pre- and postsynaptic SHANK2 functions caused by SHANK2 mutations has a strong impact on social behavior. These findings indicate that pre- and postsynaptic SHANK2 actions cooperate for normal neuronal function, and that an imbalance between these functions may lead to different neuropsychiatric disorders.


1973 ◽  
Vol 36 (3) ◽  
pp. 735-738 ◽  
Author(s):  
Joaquin F. Sousa-Poza ◽  
Robert Rohrberg ◽  
Ernest Shulman

Some characteristics of the social behavior of field-dependents as well as their superior recognition of ambiguous social stimuli led to the hypothesis that they would show greater self-disclosure than field-independents. This hypothesis was tested by administering the 60-item Jourard Self-disclosure Questionnaire (JSDQ) to 13 field-dependent and 13 field-independent Ss. In terms of total self-disclosure scores, field-dependents showed significantly (.025) higher levels than field-independents. Results are discussed in light of personality theories which emphasize the role of self-conceptual transactions in the development of the self.


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